Selective Degradation of mRNA by Herpes Simplex Virus 1
单纯疱疹病毒 1 对 mRNA 的选择性降解
基本信息
- 批准号:8255351
- 负责人:
- 金额:$ 32.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-06-10 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsActinsApplications GrantsBindingBiologyCellsCleaved cellComplexDegradation PathwayElementsEndoribonucleasesEnzymesFOS geneGenesHalf-LifeHerpes Simplex Virus Protein Vmw65Herpesvirus 1HourImmune responseInfectionLigandsMediatingMessenger RNAModelingMusPancreatic ribonucleasePathogenesisPerceptionPoly(A)-Binding ProteinsPolyribosomesProceduresProtein BindingProteinsRNARNA Cap-Binding ProteinsRecruitment ActivityRelative (related person)ReportingResearch ProposalsResidual stateRibonucleasesRoleSimplexvirusSpecificityStressStructureTIS11 proteinTestingTimeUntranslated RegionsVP 16ViralViral ProteinsVirionVirusbasebiological adaptation to stressdecapping enzymeeIF-4Bendoribonucleasefollow-upmRNA Transcript Degradationmutantprotein functionpublic health relevanceresearch studyresponsetime interval
项目摘要
DESCRIPTION (provided by applicant): Virion host shutoff protein (VHS), the product of UL41 gene of herpes simplex virus 1(HSV-1) is the major viral suppressor of host responses to infection. VHS is brought into the infected cells by the virion and its primary function is to degrade mRNA. Our studies on VHS have completely revolutionized our understanding perceptions of the functions of the protein. Specifically: (i) We have developed a procedure for solubilization and purification of VHS to homogeneity. Purified VHS is an endoribonuclease that cleaves synthetic RNA with the specificity of RNase A in the absence of cellular or viral proteins. (ii) Earlier reports indicated that at mid and late times after infection VHS is "neutralized by the viral protein VP16. We showed that "neutralization" required the formation of a complex that includes VP22 in addition to VP16. (iii) Earlier reports indicated that the degradation of mRNA mediated by VHS is nonselective. We have identified and quantified the VHS- dependent degradation of 3 classes of mRNAs as follows: Class A consists of mRNAs that are normally stable (e.g. actin, GAPDH mRNAs, normal half life >12 h). In infected cells these mRNAs are degraded 5' to 3' within 30 minutes. Class B consists of stress response mRNAs (e.g. c-fos, cox-2, I:B1 and IEX-1 mRNAs) induced immediately after infection. These mRNAs contain AU-rich elements within their 3' UTRs. Typical half life of these mRNAs in mock infected cells is 30 to 45 min. Early after infection, these mRNAs are deadenylated and cleaved 5' to AU-rich elements. The residual portions linger with a half life >3 hrs. At late times (6+ h after infection) degradation of these mRNAs is dependent on ICP27. Both class A and class B mRNAs are degraded in polyribosomes. Class C includes mRNAs that are not degraded. The products of these mRNAs include tristetraprolin, a stress inducible protein that binds to AU-rich elements and sequesters the mRNAs to exosomes for 3' to 5' degradation and GADD452 a transcriptional factor. (iv) Earlier reports indicated that VHS binds 3 components of eIF4F complex, i.e. eIF4H, eIF4B and eIF4AII and VP16. Our studies have shown that VHS also interacts physically with tristetraprolin, ICP27, and through VP16 with VP22. The objective of the research proposal is to test a model of the degradation of the mRNAs in classes A and B. The model proposes that VHS degrades mRNAs in polyribosomes as reported, that it binds to a still to be defined component of eIF4F and mimics the function of the decapping enzymes by cleaving stable mRNAs downstream of the cap structure. The residual portion is then sequestered in P-bodies and rapidly degraded. In the case of class B mRNAs, VHS binds to tristetraprolin bound to AU-rich element mRNA and cleaves the mRNA 5' to the AU-rich elements. In the absence of bound tristetraprolin, the residual mRNA is not recruited promptly for degradation 3' to 5' by exosomes. We also propose to discriminate between 2 alternative potential functions of ICP27 in enabling mRNA degradation late in infection. Finally, given the multiple functions of VHS, the question arises as to the extent to which each function contributes to the pathogenic potential of HSV-1.
PUBLIC HEALTH RELEVANCE: Cells respond vigorously to the entry of a virus into cells and Herpes simplex viruses evolved a complex strategy to block the cell from interfering with viral replication. One of the major suppressors of cellular responses is an enzyme brought into the cells by the virus that degrades mRNA made in response to infection. This grant application investigates the mechanisms by which this enzymes selectively degrades mRNA made in response to infection
描述(由申请人提供):病毒体宿主关闭蛋白(VHS)是单纯疱疹病毒1型(HSV-1) UL41基因的产物,是宿主对感染反应的主要病毒抑制因子。VHS由病毒粒子带入感染细胞,其主要功能是降解mRNA。我们对VHS的研究彻底改变了我们对蛋白质功能的认识。具体来说:(i)我们开发了一种增溶和纯化VHS的程序,以达到均匀性。纯化的VHS是一种核糖核酸内切酶,在缺乏细胞或病毒蛋白的情况下,具有RNA酶A的特异性,可切割合成RNA。(ii)早期报告表明,在感染后的中后期,VHS被病毒蛋白VP16“中和”。我们发现“中和”需要形成一个复合体,除了VP16之外还包括VP22。(iii)前期报道表明,VHS介导的mRNA降解是非选择性的。我们鉴定并量化了3类mrna的VHS依赖性降解,如下:A类由通常稳定的mrna组成(例如肌动蛋白,GAPDH mrna,正常半衰期bbb12小时)。在受感染的细胞中,这些mrna在30分钟内被降解5‘至3’。B类由感染后立即诱导的应激反应mrna(如c-fos、cox-2、I:B1和IEX-1 mrna)组成。这些mrna在其3' utr中含有富au元素。这些mrna在模拟感染细胞中的典型半衰期为30 - 45分钟。感染后早期,这些mrna被死基化并裂解成富au元素。剩余部分的半衰期为30小时。在后期(感染后6+ h),这些mrna的降解依赖于ICP27。A类和B类mrna都在多核糖体中被降解。C类包括未降解的mrna。这些mrna的产物包括tristetrprolin(一种胁迫诱导蛋白,与富au元素结合并将mrna分离到外泌体进行3‘至5’降解)和GADD452(一种转录因子)。(iv)前期报道表明,VHS结合eIF4F复合物的3个组分,即eIF4H、eIF4B、eIF4AII和VP16。我们的研究表明,VHS还与tristetrprolin、ICP27发生物理相互作用,并通过VP16与VP22发生物理相互作用。该研究计划的目的是测试a类和b类mrna降解的模型。该模型表明,VHS降解多核糖体中的mrna,它与eIF4F的一种尚待定义的成分结合,并通过切割帽结构下游的稳定mrna来模拟脱帽酶的功能。剩余部分随后被隔离在p体中并迅速降解。在B类mRNA的情况下,VHS与富au元素mRNA结合的三聚丙氨酸结合,并将mRNA 5'切割成富au元素。在没有结合的三曲丙氨酸的情况下,剩余的mRNA不能被外泌体迅速募集用于3‘到5’的降解。我们还提出区分ICP27在感染后期激活mRNA降解的两种潜在功能。最后,鉴于VHS的多种功能,问题是每种功能在多大程度上促进了HSV-1的致病潜力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bernard Roizman其他文献
Bernard Roizman的其他文献
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{{ truncateString('Bernard Roizman', 18)}}的其他基金
Optimization of Tumor Targeted HSV for Human Use
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$ 32.54万 - 项目类别:
Optimization of Tumor Targeted HSV for Human Use
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7746062 - 财政年份:2009
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Dissection of the Functions of Herpes Simplex Virus ICPO
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7834052 - 财政年份:2009
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$ 32.54万 - 项目类别:
Selective Degradation of mRNA by Herpes Simplex Virus 1
单纯疱疹病毒 1 对 mRNA 的选择性降解
- 批准号:
8458492 - 财政年份:2005
- 资助金额:
$ 32.54万 - 项目类别:
Selective Degradation of mRNA by Herpes Simplex Virus 1
单纯疱疹病毒 1 对 mRNA 的选择性降解
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7984640 - 财政年份:2005
- 资助金额:
$ 32.54万 - 项目类别:
Selective Degradation of mRNA by Herpes Simplex Virus 1
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Selective Degradation of mRNA by Herpes Simplex Virus 1
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$ 32.54万 - 项目类别:
Selective Degredation of mRNA by Herpes Simplex Virus 1
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7073978 - 财政年份:2005
- 资助金额:
$ 32.54万 - 项目类别:
Selective Degradation of mRNA by Herpes Simplex Virus 1
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$ 32.54万 - 项目类别:
Selective Degradation of mRNA by Herpes Simplex Virus 1
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